Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice
The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40 μM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the “C=C” on the seven-membered ring and “C=O” on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50 mg/kg) causes liver injury in an LPS (2 mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1β production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.
KeywordsCarbamazepine Hepatotoxicity Caspase-1 IL-1β Mitochondrial reactive oxygen species
Idiosyncratic drug-induced liver injury
Monosodium urate crystal
Mitochondrial reactive oxygen species
Pathogen-associated molecular patterns
Damage-associated molecular patterns
Dulbecco’s modified Eagle’s medium
Hank’s balanced salt solution
This work has been supported by grants from National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (2017ZX09301022, 2018ZX09101002-001-002), National Natural Science Foundation of China (81874368, 81630100, 81903891), Beijing Nova Program (Z181100006218001), Innovation Groups of the National Natural Science Foundation of China (81721002).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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